Alzheimer's Disease (AD) is the most common cause of dementia in the elderly. While acknowledging the important role of abnormal protein deposition in the pathogenesis of AD, there exists a considerable body of evidence indicating that both cerebral vascular and cerebral metabolic mechanisms play a role in the development of pathological AD and in the development of dementia in subjects with pathological AD. This project will address 3 specific aspects of these mechanisms in AD. Specific Aim 1 will test the hypothesis that patients with clinically diagnosed AD have impaired autoregulation of cerebral blood flow to reductions in systemic mean arterial pressure. Specific Aim 2 will test the hypothesis that patients with clinically diagnosed AD have an abnormality in cerebral oxidative energy metabolism. In Specific Aim 3 we will develop and optimize a method to label the synthetic amyloid peptide A-beta (1-40) with C-11 and perform animal studies to prepare for eventual studies in human subjects. The hypotheses that we will test are soundly based on mechanisms described in animal models and in vitro studies of human tissue. To bridge the gap between the laboratory bench and the patient, we will rigorously test these hypotheses in human AD in vivo by well-designed studies. This translational approach will allow us to determine the importance of these mechanisms in the human disease and potentially provide the information necessary for designing future treatment strategies. We will employ precise, accurate and well-validated techniques to measure cerebral blood flow and metabolism as well as innovative new neuroimaging techniques to evaluate brain amyloid deposition and BBB transport of amyloid. This proposal brings together accomplished investigators from the Alzheimer's Disease Research Center and the Division of Radiological Sciences with complementary expertise. Through the use of the unique resources and personnel at Washington University Medical Center, we have the opportunity to provide answers to important clinical and mechanistic questions in AD.